Inhibition of Thromboxane Synthesis Attenuates Insulin Hypertension in Rats

Chronic insulin infusion in rats increases mean arterial pressure (MAP) and reduces glomerular filtration rate (GFR), but the mechanisms for these actions are not known. This study tested whether thromboxane synthesis inhibition (TSI) would attenuate the renal and blood pressure responses to sustained hyperinsulinemia. Male Sprague-Dawley rats were instrumented with arterial and venous catheters, and MAP was measured 24 h/day. After 4 days of baseline measurements, endogenous synthesis of thromboxane was suppressed in 7 rats by infusing the thromboxane synthetase inhibitor, U63557A, intravenously (30 μg/kg/min) for the remainder of the experiment; 7 other rats received vehicle. Baseline MAP was not significantly different between vehicle and TSI rats (96 ± 1 v 99 ± 1 mm Hg). After 3 days of U63557A or vehicle, a 5-day control period was started, followed by a 7-day infusion of insulin (1.5 mU/kg/min, intravenously). Glucose (22 mg/kg/min, intravenously) was infused along with insulin to prevent hypoglycemia. In the control period, MAP was not different between vehicle and TSI rats (99 ± 2 v 100 ± 1 mm Hg), but MAP increased throughout the 7-day infusion period only in the vehicle rats with an average increase in blood pressure of 7 ± 2 mm Hg. In the control period, GFR was lower in vehicle rats compared with TSI rats (2.5 ± 0.1 v 3.1 ± 0.2 mL/min, P = .06), and the decrease to 81% ± 4% and 91% ± 6% of control, respectively, during insulin was significant only in the vehicle rats. All variables returned toward control during a 6-day recovery period. These results suggest that full expression of hypertension and renal vasoconstriction during hyperinsulinemia in rats is dependent on a normal ability to synthesize thromboxane.